PROJECT SUMMARY The incidence of chronic lung diseases such as chronic obstructive pulmonary disease (COPD) increases strongly with age, indicating that age-related alterations in the lung contribute to development and accelerated lung function decline in COPD. Indeed, aging has been demonstrated to lead to attenuated innate host defense mechanisms as well as reduced regenerative capacity, both contributing to increased infections and progressive lung destruction in COPD. The NADPH oxidase DUOX1 is prominently expressed in airway and alveolar epithelia and was recently identified as a critical component of innate host defense and maintenance of epithelial integrity. Interestingly, our preliminary studies indicate that lung tissue DUOX1 expression in mice markedly decreases with age. Furthermore, mice with genetic DUOX1-deficiency were found to display age-related features of airspace enlargement and increased lung compliance, as well as reduced alveolar macrophage responses to LPS, suggesting that DUOX1 deficiency leads to impaired epithelial regeneration and macrophage-dependent host defense against opportunistic pathogens relevant to COPD exacerbations. In addition to effects of aging, environmental factors such as tobacco smoking are major risk factor for COPD by inducing accelerated or abnormal lung aging phenomena as a critical factor in COPD development. Intriguingly, recent studies indicate reduced lung epithelial DUOX1 expression in healthy smokers and COPD patients, and experimental studies show that chronic exposure of mice to cigarette smoke or acrolein (one of its major harmful components) results in loss of airway DUOX1 expression. Moreover, loss of DUOX1 expression was also found to be associated with enhanced features of airway remodeling, characterized by epithelial-to-mesenchymal transition (EMT) and subepithelial fibrosis, important pathological features COPD. These various findings indicate that progressive loss of DUOX1, as a combined result of chronic tobacco smoke exposure and aging, contributes to important features of COD pathology, by minimizing epithelial repair capacity and innate host defense mechanisms and by enhancing airway remodeling and small airway fibrosis. The present proposal will explore mechanistic relationships between DUOX1 silencing and biological aging, and the relevance of DUOX1 suppression for age- related emphysema in an experimental model of elastase-induce emphysema (Aim 1). Secondly, we will determine the impact of DUOX1-deficiency on epithelial remodeling and subepithelial fibrosis induced by chronic acrolein exposure. Overall, these studies will address combined effects of smoking and age on DUOX1 as an example of gene-environment interactions in the disease pathology of COPD.